A novel class of compounds has been found to be effective in treating hyperlipidemia, obesity and impaired glucose tolerance/noninsulin dependent diabetes mellitus without adversely affecting energy metabolism. The active compounds have the general formula 
R1-R4 each independently represents a hydrogen or an unsubstituted or substituted hydrocarbyl or heterocyclyl radical;
where R5 and R6 independently represent hydrogen, hydroxyl, lower alkyl, chloro, bromo, cyano, nitro, lower alkoxy, or trifluoromethyl
Q represents a diradical consisting of a linear chain of 2 to 14 carbon atoms, one or more of which may be replaced by heteroatoms, said chain being optionally substituted by inert substituents and one or more of said carbon or heteroatom chain members optionally forming part of a ring structure and where one or both of the carboxyl groups can be substituted by an in vivo hydrolyzable physiologically acceptable substituent.
The invention also provides pharmaceutical compositions comprising the aforementioned compounds of formula (I) for the treatment of obesity, hyperlipidemia and maturity-onset diabetes.
Dyslipoproteinemia (combined hypercholesterolemia-hypertriglyceridemia), low HDL-cholesterol), obesity (in particular upper body obesity), impaired glucose tolerance (IGT) leading to noninsulin-dependent diabetes mellitus (NIDDM)) and essential hypertension are common diseases that afflict individuals living in Westernized societies. Being initiated and linked through hyper-insulinemia these four diseases often coexist and precipitate independently as well as synergistically atherosclerotic vascular disease leading to coronary heart disease. The incidence of the Deadly Quartet (Syndrome-X, Metabolic Syndrome) comprising the four diseases increases as the population ages and by 70 years of age reaches epidemic proportions. Combatting the individual categories of the Deadly Quartet as well as offering a whollystic therapeutic approach to the Syndrome is considered one of the most important challenges of medicine in affluent Westernized society.
Many hypercholesterolemic/hypertriglyceridemic individuals turn out as low- or non-responders to dietary measures and therefore are candidates for long-term treatment with hypolipidemic drugs. HMG-CoA reductase inhibitors and bile acid sequestrants designed to upregulate the LDL receptor are very effective in isolated hyper-cholesterolemia. However, both are ineffective in reducing plasma triglycerides and poorly effective in increasing plasma HDL, thus being short of offering an adequate treatment mode for combined hypertriglyceridemia-hypercholesterolemia (which comprise of  greater than 70% of dyslipoproteinemic patients) or for isolated hypertriglyceridemia with reduced plasma HDL, as well as for the postprandial chylomicrons-rich phase realized now as an independent risk for atherosclerotic cardiovascular disease. Isolated hyper-triglyceridemia may however be treated with either nicotinic acid or drugs of the fibrate family. However, the compliance for nicotinic acid is very poor and the advantage of fibrate drugs in lowering overall mortality has been seriously questioned since the exhaustive WHO clofibrate study. Also, nicotinic acid is ineffective while fibrate drugs are only poorly effective in reducing plasma cholesterol, thus leaving the combined hypertriglyceridemic-hypercholesterolemic patient with the only choice of a combination treatment mode (e.g., HMG-CoA reductase inhibitor/nicotinic acid).
Weight reduction measures are essentially based on promoting dietary or behavioral means for reducing weight. However, most obese individuals turn out to respond inadequately to dietary or behavioral measures, especially if examined over long time periods. The chances for 5-year maintenance of weight reduction initiated by dietary and behavior modifications are less than 10%. This overwhelming failure is mainly metabolic, since the decrease in weight as a result of dieting is always accompanied by a decrease in basal metabolic rate and overall energy expenditure, thus forcing the dieting obese patient into a genuine deadlock. Antiobesity drugs based on modulating energy intake are currently based on anorectics designed to depress the hypothalamic satiety center. These drugs are reported to be ineffective in the medium and long range and some may induce primary pulmonary hypertension. Similarly, no antiobesity drugs are presently available based on modulating total body calorie expenditure while allowing free access Lo calorie consumption. Peripherally acting thermogenic xcex23-adrenergic agonists are selected on the basis of their capacity to stimulate brown adipose tissue xcex2-adreno receptors and may indeed induce thermogenesis in rodents. However, the efficacy of such agents in humans while allowing free access to calories is still questionable and their broad tissue specificity (e.g. skeletal muscle, myocardium, colon) may be expected to result in nonspecific-adrenergic-induced effects.
Presently available pharmacological measures for treating IGT and overt NIDDM consist of two oral hypoglycemic drug types which are in use for over 30 years. The sulphonylureas promote pancreatic insulin secretion for coping with peripheral insulin resistance, while biguanides are claimed to improve peripheral insulin action. The popularity of sulphonylurea does result from the old conviction that blood glucose which precipitates the diabetic microvascular disease in retina. kidney, nerve and some other tissues should be normalized by all means even at the expense of increased pancreatic insulin secretion. This therapeutic approach was initiated in times when the hyperinsulinemic phase dominating the natural history of the development of NIDDM or the course of obesity-induced IGT was not realized, neither the pathological sequel dictated by sustained hyperinsulinemia. Moreover, the sulphonylurea (similarly to insulin) tend to promote weight gain, thus further promoting insulin resistance and compensatory hyperinsulinemia leading to diabetes-induced macrovascular disease (atherosclerotic cardiovascular disease). Biguanides are claimed to potentiate insulin-mediated glucose disposal with no stimulation of pancreatic insulin secretion. However, the use of biguanides as monotherapy is not unanimously recommended except for the very obese in light of their low therapeutic/toxicity index and the induction of lactic acidosis. During the period of the last ten years, the scientific community became progressively aware of the etiological-pathophysiological linkage between dyslipo-proteinemia, obesity, NIDDM, hypertension, decreased fibrinolysis and some ocher pathologies (e.g., hyperuricemia), realizing now that the concerned pathologies are just reflections of a unifying Syndrome. Leading to atherosclerotic cardiovascular disease, the Syndrome is realized now to be the major risk factor for mortality and morbidity in Western Societies Treating the Syndrome pharmacologically calls for an whollystic approach rather than dealing separately with each of its distinct categories. No drug designed alongside these principles is yet available.
xcex1,xcfx89-Dialkanoic acids of chain length of 14 20 carbon atoms which are hydrocarbyl substituted on the xcex2,xcex2xe2x80x2carbon atoms, as well as their salts and ester derivatives were disclosed in Bar-Tana U.S. Pat. Nos. 4,634,795, 4,689,344 and 4,711,896 as possessing a hypolipidemic, weight reducing and antidiabetogenic activity. Realizing however that treatment of the Metabolic Syndrome and its related pathologies would require chronic dosing has initiated an exhaustive search for new compounds having a higher efficacy as compared with the previously disclosed xcex2,xcex2-substituted xcex1,xcfx89 dialkanoic acids.
A novel class of compounds has now been found, in accordance with the present invention, to be surprisingly effective in reducing blood lipids. The new compounds of the invention were also found to have a calorigenic antidiabetic (NIDDM) activity without adversely affecting energy metabolism. Furthermore, the efficacy of some of these compounds is far better as compared with previously reported xcex2,xcex2xe2x80x2-substituted xcex1,xcfx89-dialkanoic acids. The novel compounds provided by the present invention are xcex1,xcfx89-dialkanoic acids having the general formula 
and in vivo hydrolysable functional derivatives of the carboxylic groups thereof, wherein R1-R4 each independently represents a hydrogen or an unsubstituted or substituted hydrocarbyl;
where R5 and R6 independently represent hydrogen, hydroxyl, lower alkyl, chloro, bromo, cyano, nitro, lower alkoxy, or trifluoromethyl;
Q represents a diradical consisting of a liner chain of 2 to 14 carbon atoms, one or more of which may be replaced by heteroatoms, said chain being optionally substituted by inert substituents and one or more of said carbon or heteroatom chain members optionally forming part of a ring structure.
Included within the scope of the invention are those derivatives of the xcex1 and/or xcfx89 carboxy groups of the compounds of formula I above, which are capable of being hydrolyzed in vivo to yield the free diacids of formula I. Among such suitable derivatives there should be mentioned, in the first place salts with pharmaceutically acceptable inorganic or organic cations, in particular alkali metal salts, alkaline earth metal salts, ammonium salts and substituted ammonium salts; esters, particularly lower alkyl esters: amides, mono- and di-substituted amides; and anhydrides, e.g., with lower alkanoic acids; and lactones formed by ring closure of either or both carboxylic groups with a free hydroxy substituent (or substituents) in the molecule of formula (I).
The term xe2x80x9chydrocarbylxe2x80x9d in the definition of R1-R4 includes, e.g., optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, optionally substituted aryl, optionally substituted aralkyl and the like.
A preferred group of compounds in accordance with the invention are those of formula (I) above in which R1-R4 are each lower alkyl and Q is a straight polymethylene chain of 2 to 14 carbon atoms; and in vivo hydrolysable functional derivatives thereof.
Especially preferred compounds of the present invention are those of the general formula 
and their in vivo hydrolysable functional derivatives, wherein n is an integer from 6 to 12;
or of the general formula 
where n is an integer from 10-16; and their in vivo hydrolyzable function derivatives.
The novel compounds of formula (I) according to the invention, can be prepared by methods known per se, some of which are illustrated in the examples herein.
In another aspect, the present invention provides pharmaceutical compositions for the treatment of obesity, hyperlipidemia, diabetes or the Metabolic Syndrome, comprising as active ingredients the novel compounds of formula (I) above together with pharmaceutical carriers or diluents. The pharmaceutical compositions are primarily for oral administration, but may also be for parenteral or topical administration. These pharmaceutical compositions, which are preferably in dosage unit form, may be in the form of, e.g., tablets, capsules, lozenges, pills, powders and aqueous and non-aqueous solutions or suspensions. The pharmaceutical compositions of this invention preferably comprise also conventional pharmaceutical solid or liquid carriers or diluents, e.g., gelatin, sugars, starches, cellulose derivatives, fatty acids and their salts, vegetable oils, glycerine, glycols, water, aqueous saline or phosphate buffer solutions and the like. The compositions may also comprise other compatible substances normally used in pharmaceutical formulations and also other additives, such as colouring agents, flavouring agents and preservatives.
The pharmaceutical compositions according to the invention are preferably in dosage unit form, each unit containing from 50 to 500 mg of the active ingredient of the formula (I) above. The daily dosage of the compounds of formula (I) above according to the invention will depend on the age, needs and tolerance of the individual patient, but will usually range from 50 mg to from 5,000 mg per day. The pharmacological activities of the compounds of formula (I) according to the invention could be demonstrated by means of in vivo experiments in rats and in vitro experiments in liver cells in accordance with standard methods. Some of these experiments are described hereinafter in detail.
Experiment I
Rats (n=5 for each treatment group) were fed ad libitum on Purina chow for 6 days, the diet being supplemented with 0.1% (w/w) xcex3,xcex3xe2x80x2-methyl substituted xcex1,xcfx89-dioic acids of formula (II) (Ex. 1, Ex. 3, Ex. 4) in the diet. The biological effect in vivo was evaluated by following food intake, plasma triglycerides, plasma cholesterol and plasma glucose. The results are shown in the following Table I.
Experiment II
Rats (n=5 for each treatment group) were fed ad libitum on purina chow for 5 days, the diet being supplemented with either xcex3,xcex3xe2x80x2-methyl substituted xcex1,xcfx89 hexadecanedioic acid (formula (II). Ex. 3) or xcex2,xcex2xe2x80x2-methyl substituted xcex1,xcfx89-hexadecanedioic acid (U.S. Pat. No. 4,634,795) at a dosage of 0.09% (w/w) in the diet. The biological effect in vivo was evaluated by following plasma triglycerides, plasma apolipoprotein(apo)C-III, plasma insulin and the steady state concentrations (Css) of the respective drugs in plasma. Fold efficacy of the xcex3,xcex3xe2x80x2-substituted compound (Ex. 3) relative to the xcex2,xcex2xe2x80x2-substituted compound was calculated by normalizing the observed effect by the respective Css attained. The results are shown in the following Table II
Experiment III
Conditions as in Experiment II using xcex1,xcex1xe2x80x2-methyl-substituted xcex1,xcfx89-tetradecanedioic acid. The results are shown in the following Table III.
Fold efficacy represents the respective effect induced by the xcex1,xcex1xe2x80x2-substituted compound (Ex. 5) relative to that of the xcex2,xcex2xe2x80x2-substituted compound.
Experiment IV
Uncoupling of oxidative phosphorylation by compounds of formula I was evaluated in isolated liver cells loaded with JC-1 dye (as described by M. Reers et al., Meth. Enzymol. 260, 406 (1995))) and incubated in the presence of added compounds of formula I as specified JC-1 fluorescence was determined by FACSCAN flow cytometry. While the cytosolic monomeric dye emits at 530 nm (when excited at 488 nm), the fluorescence of the intramitochondrial aggregated dye shifts to 590 nm. The 530/590 fluorescence ratio thus reflects the cytosolic/mitochondrial distribution of the dye as a result of the prevailing mitochondrial inner membrane potential of affected cells. The higher the 530/590 ratio the higher the extent of uncoupling and calorigenesis induced by added effectors. The results are shown in the following FIG. 1.
The following conclusions were reached with regard to the biological effects of compounds of formula I:
(a) The active compounds are potent hypolipidemics. The overall hypolipidemic effect is based on activating plasma lipoproteins clearance resulting from decrease in plasma apo C-III.
(b) The active compounds are potent insulin sensitizers as reflected by plasma insulin concentrations required for maintaining euglycemia. Insulin sensitization may form the basis for using these compounds in the treatment of IGT/NIDDM.
(c) The active compounds induce increase in calorigenesis as a result of decrease in mitochondrial membrane potential. Uncoupling induced by these compounds may form the basis for using these compounds in the treatment of obesity.
(d) These compounds may offer an whollystic therapeutic approach for the Metabolic Syndrome. Their efficacy is far higher as compared with homologous xcex2,xcex2xe2x80x2-substituted compounds.